Propofol is an intravenous anesthetic agent characterised by a short recovery time. It has the desirable property of rapid onset and offset of the anaesthetic effect following intravenous administration and minimal accumulation on long-term administration.
Propofol even though is a preferred anesthetic agent, has posed a big challenge to the formulator since its invention because of its aqueous insolubility. It was at first formulated as a 1% aqueous solution containing nonionic surfactant Cremophor EL as a solubiliser. However, Cremophor EL has been implicated in some adverse reactions when administered intravenously, including anaphylactoid reactions.
Subsequently, the anaesthetic agent was formulated as oil-in-water emulsion containing 1% w/v propofol with 10% w/v soybean oil & 1.2% w/v purified egg phosphatide. Lipid based emulsions suffer from several limitations such as poor physical stability, the potential for embolism, pain on injection and increased fat load. Furthermore, strict aseptic techniques must be maintained when handling these formulations since they contain no antimicrobial preservatives and therefore can support rapid growth of microogranisms.
G. Trapani et al (J.P.S. April 1998, 87(4), 514–518) have studied the physicochemical and anaesthetic properties of a freeze dried inclusion complex of propofol with 2-hydroxypropyl-β-cyclodextrin in 1:1 mol/mol (1:8 wt./wt) stoichiometry. In this process, complex formation was achieved after continued stirring for five days.
Pharmaceutical compositions comprising inclusion complex of propofol and 2-hydroxypropyl-β-cyclodextrin have been described in a WO 96/32135. At the ratio of propofol to 2-hydroxypropyl-β-cyclodextrin 1:1.5 to 1:<2 mol/mol (1:11.79 to 1:<15.72 wt./wt.), additional co-solvent was necessary to formulate a clear colourless solution. At 1:2 to 1:2.5 mol/mol stoichiometry (1:15.72 to 1:19.65 wt./wt.) solution was clear. However we find that such solutions are not stable to autoclaving.
Preferred process of sterilisation specified in pharmacopoeias is autoclaving of the product in the final container. Further as propofol is commonly administered by intravenous route to induce and maintain general anaesthesia, terminal sterilisation is the only preferred alternative which offers higher confidence of sterility compliance.
Our main objective of this invention is thus to develop a clear aqueous composition of propofol complexed with HPBCD that is stable to autoclaving thereby making it suitable for parenteral administration in human beings and other mammals.